The general objective of this project is to define the mechanisms by which human lymphoid cells interact with each other and with foreign antigen-bearing cells in order to produce and regulate immune responses. Over the past year, there have been two major efforts underway that are targeted on this objective: 1) dissection of the molecular basis for T cell recognition of class I HLA gene products; and 2) analysis of the potential role of human T cell receptor (TcR) beta chain genes in susceptibility to multiple sclerosis (MS). The definition of the structural features of class I HLA molecules that are important for T cell recognition and antigen presentation has been pursued using site-directed mutants of HLA-A2 and HLA-A3 genes. The results of these studies demonstrate that: 1) for both HLA-A2 and HLA-3, the amino acid at position 152 on the alpha two helix is of critical importance for recognition by both virus-specific and alloreactive CTL; 2) recognition by viral peptide-specific CTL is abrogated by amino acid substitutions at either position 152 or 156 of the HLA-A2 molecule; and 3) these amino acid substitutions if the putative peptide binding site of the HLA-A2 molecule can affect presentation without eliminating peptide binding, indicating that the failure to recognize complexes between the peptide and the mutant HLA-A2 molecules is due to different TcR specificities and not to the failure to bind the peptide. Analysis of TcR beta chain gene haplotypes defined by V-beta 8 and V-beta 11 alleles in 40 chronic progressive MS patients revealed a significantly different distribution from that seen in the normal population (P=0.012). These results suggest that there may be an MS susceptibility gene(s) in this region of the TcR beta chain locus.